Vaccination represents one of medicine's most successful innovations. At the time that the polio vaccine was first introduced in the United States, more than 20,000 new cases of paralytic polio were reported annually. Today, the number of new cases approaches zero. Similar results have been obtained for measles, mumps, diphtheria, pertussis, and tetanus (Hinman, Vaccines, pp. 597, 595, S. Plotkin & E. Mortimer, Jr. ed., 1988). On a global level, vaccination has resulted in the eradication of smallpox (World Health 34:258(1980)).
Despite these successes, there are many diseases that are not prevented by vaccination. Among the most important of these is AIDS. Although immunization probably offers the best hope of stemming the spread of this disease, particularly in developing countries, the development of an effective vaccine against AIDS has proven extraordinarily difficult. Among the many reasons that vaccines fail is that the antigens associated with a pathogen are only weakly immunogenic or that antigens mutate and assume new forms.
In general, vaccines have been prepared using whole, live, attenuated, heat or chemically killed bacteria or viruses, whole protein or peptide fragments, DNA, or purified polysaccharides. Polypeptides typically lead to T cell activation and prime a treated individual to secondary challenge, i.e., the individual responds more strongly if exposed to the same antigen at a later time. Unfortunately proteins and peptides often require the co-administration of adjuvants that may be toxic and stimulate the immune system in a non-specific way. Unlike proteins, polysaccharides are often capable of directly stimulating B cells to produce antibody without the need for T cell help. However, the response they generate tends to be relatively short and there is no priming to subsequent antigenic challenge.
In the last several years, attempts have been made to develop vaccines with improved properties by covalently coupling polypeptides and polysaccharides (see e.g. U.S. Pat. Nos. 5,773,007; 5,968,521; 5,866,135; 4,619,828). Initial successes with these vaccines led to improved methods for carrying out coupling reactions (U.S. Pat. Nos. 5,651,971; 6,248,334). As a result of these efforts, at least two conjugate vaccines are presently on the market; one for Haemophilus influenza type B infections (HibTITER®) and the other for pneumococcal diseases (Prevnar®). In both cases, the vaccines comprise an antigenic polysaccharide covalently bound to a diphtheria toxoid that enhances a patient's immune response. Additional improvements in the design of conjugates may lead to better vaccines and allow vaccination to be used for a wider range of diseases.